Iron-Based Olefin Metathesis Catalysts

描述（由申请人提供）：治疗剂的制备主要依赖于化学家构建各种有机分子的能力。由于许多药物含有复杂的碳骨架，因此选择性偶联两个碳部分的过程至关重要。最有效和选择性的碳-碳键形成方法之一是铼催化的烯烃复分解反应。由于铁是廉价的并且具有低毒性，显著的技术进步将是设计铁基烯烃复分解催化剂。制备这样的催化剂将需要合成迄今未知的低配位铁亚烷基。作为起始点，将制备式Cl 2（L）Fe=C（H）R的中性亚烷基铁（II），其中L是环状氨基卡宾配体。与通常为低自旋的钌亚烷基相反，铁络合物Cl 2（L）Fe=C（H）R可以高自旋状态存在。由于在过渡金属中心的所有d轨道中存在至少一个电子，高自旋C12（L）Fe=C（H）R络合物可以抵抗烯烃配位，因此延迟复分解活性。该潜在问题的解决方案将是合成XCl（L）Fe=C（H）R和X2（L）Fe=C（H）R络合物，其中X是CN-或C6 F5-基团。用这些较强的场配体取代Cl 2（L）Fe=C（H）R的Cl-基团将增加系统中的配体场分裂参数，这将促进更有利于烯烃配位的较低自旋状态。为底物结合提供可接近的配位位点的另一种方法是通过氯化物提取使Cl 2（L）Fe=C（H）R络合物呈阳离子。得到的XCI（L）Fe=C（H）R和X2（L）Fe=C（H）R，其中X是极非配位的抗衡离子，例如B（C6 F5）4-或HBCl 11 Cl 11-，在溶液中应解离以分别形成形式上12和10电子的铁单阳离子和双阳离子Cl（L）Fe=C（H）R+和（L）Fe=C（H）R2+。一种不同的方法是制备中性铁（O）亚烷基。可显示复分解活性的理想铁（0）物质将是（R3 P）LFe=（H）R。这类络合物应该能够在溶液中解离膦配体，以提供具有至少两个空配位位点的LFe=（H）R片段，而与金属的自旋状态无关。本研究提案的最终目标是为合成界提供廉价、环境友好、高活性和选择性的烯烃复分解催化剂。公共卫生相关性拟议的研究计划旨在使用铁化合物提供方法，使药物以更环保和更具成本效益的方式生产。因此，这项工作可能最终提供清洁的方法来生产更便宜的药物。

DESCRIPTION (provided by applicant): The preparation of therapeutics relies largely on the ability of chemists to construct a wide range of organic molecules. Since many pharmaceuticals contain a sophisticated carbon skeleton, processes that selectively couple two carbon moieties are of paramount importance. One of the most efficient and selective carbon-carbon bond forming methods is the ruthenium-catalyzed olefin metathesis reaction. Since iron is inexpensive and has a low toxicity, a significant technological advance would be to design iron-based olefin metathesis catalysts. Preparing such catalysts will require the synthesis of hitherto unknown low-coordinate iron alkylidenes. As a starting point, neutral iron(ll) alkylidenes of the formula CI2(L)Fe=C(H)R, where L is a cyclic amino carbene ligand, will be prepared. In contrast to ruthenium alkylidenes that are typically low-spin, iron complexes CI2(L)Fe=C(H)R may exist in a high-spin state. Due to the presence of at least one electron in all of the d-orbitals of the transition metal center, high-spin CI2(L)Fe=C(H)R complexes may resist olefin coordination, consequently retarding metathesis activity. A solution to this potential problem would be to synthesize XCI(L)Fe=C(H)R and X2(L)Fe=C(H)R complexes, where X is a CN- or C6F5- group. Replacement of the CI- groups of CI2(L)Fe=C(H)R by these stronger field ligands will increase the ligand field splitting parameter in the system, which should promote a lower-spin state more favorable for olefin coordination. Another approach to providing accessible coordination sites for substrate binding would be to render CI2(L)Fe=C(H)R complexes cationic by chloride abstraction. The resultant XCI(L)Fe=C(H)R and X2(L)Fe=C(H)R, where X is an extremely non-coordinating counterion such as B(C6F5)4- or HBC11Cl11-, should dissociate in solution to form the formally 12 and 10 electron iron mono and dications CI(L)Fe=C(H)R+ and (L)Fe=C(H)R2+, respectively. A different approach would be to prepare neutral iron(O) alkylidenes. An ideal iron(0) species that may display metathesis activity would be (R3P)LFe=(H)R. Complexes of this class should be capable of dissociating the phosphine ligand in solution, to afford LFe=(H)R fragments with at least two vacant coordination sites, independent of the spin state of the metal. The ultimate goal of this research proposal is to provide the synthetic community with inexpensive, environmentally benign, highly active and selective olefin metathesis catalysts. PUBLIC HEALTH RELEVANCE The proposed research plan intends to use iron compounds to provide methods that allow pharmaceuticals to be produced in a more environmentally friendly and cost effective manner. Thus, this work may ultimately provide clean methods to produce cheaper medicines.